With the increasing age of the global population, stage IV colorectal cancer is being diagnosed in elderly patients more frequently than ever before [10]. As a result of extensive progress in surgical and anesthetic techniques and modern chemotherapy regimens, more patients can undergo resection of liver metastases with curative intent. This has been proven to be the most effective treatment strategy for colorectal liver metastases (CRLM). However, the increasing possibility of age-related comorbidities and high ASA scores among the elderly patients undergoing hepatectomy poses a higher risk of postoperative morbidity and mortality. Most recently, a multidisciplinary consensus from Italy pointed out the potentially negative impact of old age on recovery of patients from damage. The consensus also put forward some useful evaluation benchmarks for the elderly before operation, which would be critical for the selection of the elderly patients for surgery in the future[21]. Although some previous literature reported that older patients had similar surgical safety and long-term survival compared with younger patients, baseline data for both groups were not balanced. Some important prognostic factors such as RAS/BRAF mutation and primary tumor sidedness were also not included in published studies. Therefore, this study, which compared the short-term and long-term results of hepatectomy for younger and elderly patients, was designed to overcome the above-mentioned drawbacks.
There are different definitions in the literature as to the cutoff age for an individual to be designated as elderly [11, 15-18, 20]. However, the most frequently used cutoff age is 70 [15, 16, 22-24], which was adopted for the EG cutoff in this study. Due to the unmatched demographic and preoperative treatment data between the EG and the YG in this study, a PSM method was used to probe the effect of age on patient outcomes after hepatectomy. Vito De Blasi et al. [20] also used this method to mitigate potential biases between groups. However, despite the PSM approach, there were still some unmatched parameters between the groups – namely pedicle clamping duration and recurrence treatment protocol – which resulted in some inconclusive analyses. Furthermore, most previous studies have enrolled patients with EHD, which makes accurate definition of DFS challenging. To overcome this disadvantage, we excluded all patients with EHD from analysis in this study.
Before propensity score matching, there were biases in the baseline data between the EG and the YG due to differences in comorbidities and ASA scores. In addition, some perioperative factors – such as the proportion of patients who had >3 liver metastases, received more than six cycles of preoperative chemotherapy, received postoperative chemotherapy or underwent intraoperative RFA – were also significantly different between the YG and EG. Importantly, it has been reported that more than six cycles of preoperative chemotherapy and intraoperative RFA may increase postoperative morbidity; furthermore, having >3 liver metastases and receiving postoperative adjuvant chemotherapy are important prognostic factors for patients with CRLM [25, 26]. Propensity score matching was used to balance the distribution of these variables between groups in this study. After matching, short-term patient outcomes revealed that the EG had significantly less intraoperative blood loss and a shorter postoperative hospital stay – though a higher readmission rate – compared to the YG. Long-term outcomes demonstrate a slight, but non-statistically significant improvement, in 5-year DFS, OS and CSS for the EG compared with the YG.
For modern treatment of CRLM, routine testing of RAS/BRAF mutation status has been recommended since 2014 as it has been confirmed to be a negative prognostic factor for CRLM patients [27]. It has been reported that positive RAS/BRAF mutation status is associated with shorter DFS and OS and narrower margin widths after hepatectomy compared to wild type RAS/BRAF [28-30]. However, RAS/BRAF mutation status has never been considered in previous retrospective studies, as much of the data precedes standard testing for RAS/BRAF status. In this study, all tumor tissue samples from the considered patients were retrieved from the pathology department and tested for RAS/BRAF mutation status, which was matched between the two groups after PSM.
Primary tumor sidedness has also been emphasized in recent years in recognition of the fact that the side of origin plays a role in tumor behavior and progression. It was reported that tumors originating on the right were more frequently associated with female patients, the elderly, high grade (poor differentiation), BRAF mutations, the enhanced CpG island methylator phenotype, high microsatellite instability and high expression of consensus molecular subtypes 1 and 3 compared with left-side origin tumors [31]. These characteristics negatively affect anti-EGFR treatment and the prognosis of patients with right-sided tumors [32]. Therefore, we included primary tumor sidedness in our PSM model to balance the possible bias associated with this disease feature.
The CRS was proposed in 1999 by Fong et al. [33] as a prognostic indicator composed of five preoperative variables: preoperative CEA > 200 ng/mL, primary positive lymph nodes, an interval of <12 months between diagnosis of the primary tumor and liver metastasis, presence of multiple liver metastases and maximal diameter of liver metastases >5 cm. It has been shown that increased CRS is associated with an increased risk of postoperative recurrence and death [34]. Thus, it was important to include CRS in our PSM analysis to appropriately examine the effect of age on survival.
This study revealed no significant difference in either general or surgical postoperative complications between the EG and the YG. This result aligns with previous studies and suggests that surgery for elderly patients is as safe as it would be for younger patients with the same ASA score and comorbidities [20, 35]. This holds even when simultaneous resection of primary and liver tumors or major hepatectomy is performed. Interestingly, compared to the YG, the EG was found to have significantly less intraoperative blood loss (175 mL vs. 200mL, p=0.046) and a shorter median postoperative hospital stay (8 days vs. 11 days, p=0.020), which might reflect that appropriately selected elderly recover promptly from surgery. However, the EG group did have a significantly higher readmission rate than the YG (4.7% vs. 0%, p=0.036). Although the median intraoperative blood loss of the YG is higher than that of the EG, an absolute difference of 25 mL is of little clinical significance. The significance of the difference between groups may result from the relatively small sample size of this study, considering the p value approaching 0.05. With a larger sample size and improved matching between the groups with regards to perioperative details – such as preoperative chemotherapy, major hepatectomy, simultaneous resection and Pringle clamping time – the intraoperative blood loss will likely be comparable between the EG and the YG.
The three patients from the EG who were readmitted to the hospital were all 71 years of age. The first patient was diagnosed with synchronous descending colon cancer with liver metastases and received simultaneous resection of the primary tumor and liver metastases. The patient was readmitted due to incisional infection two months after discharge. The second readmitted patient was diagnosed with bilobar liver metastases after resection of sigmoid colon cancer. He was readmitted to the hospital one month after liver resection due to a fever of 38.3℃. Laboratory tests showed a normal white blood cell count, and radiological examinations revealed no signs of abdominal or thoracic collection. The third readmitted patient was diagnosed with multiple liver metastases after resection of ascending colon cancer. He received hepatectomy and intraoperative RFA for multiple tumors. He was readmitted to the hospital 2 months after operation due to fever of 38.5℃. The white blood cell count was marginally elevated, and ultrasound showed a small thoracic collection without abdominal fluid. In brief, although three patients from the EG were readmitted to the hospital, only one of them experienced an unequivocal surgical complication (incisional infection), which classified as a minor complication. None of the readmitted patients experienced systemic complications related to old age. When the length of hospital stay after readmission was added to the length of the postoperative hospital stay, the median total length of postoperative hospital stay was still significantly longer in the YG than in the EG (11 days vs. 8 days,p=0.024). As such, we do not believe that the EG’s length of stay advantage compared to the YG was offset by the higher readmission rate.
With regards to the median length of postoperative stay being shorter in EG patients compared to YG patients, we found that the proportions of major hepatectomy and grade III or higher postoperative complications were much higher in the YG than the EG (18.8% vs. 12.5% and 56.8% vs. 29.4%, respectively), although this was not statistically significant. Given the relatively small sample size of our study, the significantly shorter postoperative length of stay in the EG may result from these differences. Thus, this result should be clarified in larger studies in the future. Regarding long-term patient outcomes, surprisingly, the 5-year DFS, OS and CSS rates were increased by 5.6%, 12.7% and 15.1%, respectively, for the EG compared to the YG, although these differences were not statistically significant. Importantly, it was shown that the OS and CSS of the YG were longer than those of the EG prior to PSM. This discrepancy may arise due to the following factors. First, some research [36, 37] has shown that the malignancy of tumors in the elderly population may be reduced; thus, the potential for tumor growth and metastasis may be decreased in the elderly as well. Second, some factors such as RAS/BRAF mutation status, primary tumor sidedness and history of preoperative chemotherapy were included in our study and balanced between the EG and YG by PSM. These important prognostic factors were lacking in previously published studies, which may contribute to the difference in OS identified in our study. Notably, due to the relatively small sample size of this study, this conclusion should be confirmed by high-quality studies with a larger sample size in the future.
This study has some limitations. First, similar to other studies, this study had a relatively small sample size. After eliminating patients with EHD and unmatched patients, there were only 64 patients in the EG and 128 patients in the matched YG considered for analysis, which may impact the representativeness and robustness of the results. As such, the results of this study should be confirmed by high-quality studies with larger sample sizes in the future. Another limitation is the retrospective nature of this study; so the conclusion should be evaluated by large prospective controlled trials in future work. The third limitation is the loss of information regarding the response to preoperative chemotherapy as a referral center, which has been shown in previous work to be a pivotal prognostic factor for CRLM patients undergoing hepatectomy [34, 38]. Finally, the fourth limitation was that the chemotherapy regimes had changed during so long study interval. Actually, preoperative and postoperative chemotherapy backbone drugs of the younger group were not significantly different from those of the elderly group as shown in the Table 3. However, the detailed chemotherapy regimes were very difficult to be balanced between the two groups.